Therapeutic arsenic preparation



Patented May-23, 1944 Russell Hopkinson, East Hampton, and Alexander V.TolstoouhonNew York. N. Y., assignors, by mesnc assignments, to Parke,Davis a Company, Detroit, Mich, a corporation of Michigan No Drawing.

Application August 2.4, 1940, Serial N0. 354,120

Claims. (cl. rel-s9) The present invention relates to pharmaceuti calproducts composed ofor containing organic compounds "of trivalentarsenic and having This application is a continuation-in-part of ourapplication,.Serial No. 259,86,-filed March More specifically, ourinvention relates to the spirocheticidal and trypanosomicidalproperties.

bufier ,agent such as sodium -citrate, sodium succinate .or sodiummalonate. In the broader aspects of the invention the buffer agentswhich may be used include--,

1.The alkali metal salts of the polybasic acids, preferably citric,succinic; malonic, tarmanufacture of improved pharmaceuticalpreparations by the use of the hydrochlorides ofamino-aryl-dichloro-arsines and of amino-arylarsine oxides, preferablyin the dry, solid form, which preparations are of'improved stability andare capable of yielding aqueous solutions of novel composition andimproved properties. The inventionis, however, not limited to drypreparations but includes also aqueous solutions within certain pHranges, as will be described more fully below.

Briefly described, our invention involves the stabilization ofarsenicalcompounds by compounding or associating therewith, preferably in the drycondition, buifer compoundssuch that aqueous solutions will be obtainedtherewith which are within predetermined pH ranges, the

and in the water solution of theimi'xtureydecreased pain on injection,and simplicity in solid preparations 'and the solutions having numerousadvantages both from the clinical and manufacturing standpoints overprior arsenicalpreparations which yield strongly acid solutions, as willbe set out in detail hereinafter.

In-the present state of the artit is known that trivalent arsenicalcompounds may be astaric, and phthalic acids, and I 2. Mixtures of oneor more of said salts with sodium carbonate or'dior tri-sodiumphosphate- Among the advantagesof ournew preparations are improvedstability, both inthe dry mixture manufacture. The bufier' agents, aboveenumerated, 'when used in two to fivetimes the weight of the arsenicalproduce in aqueous solution a pH'of from 4.5 tonotove'r 6.5 whether thesolution be saturated or dilute as 1' in 10,000.

. Preferably, the bufler agent is present in a greater than equivalentproportion to that-of the arsenical. I

Aparticular advantage in the use of the citrate,

succinate'or malonate is that a 1.5% solution is isotonic with'bodyfluids, and this is a very satisfactory strength for producing thecorrect pH andadequate bufier effect in connection with an average dose:of either oi the above named arsenicals. I

A further advantage of the above mentioned bufler-agents is that thedesired pH of the solutlon may be obtained without exact measurementsociated with a neutralizing agent, such as sodium carbonate, in a drypowdered mixture which, when dissolved in'water, forms .atherapeutically useful solution suitable .for intra-z venous injection.United States Patent No.

2,092,028, issued September '7, 1937, describes a v mixture of3-amino-4-hydroxy phenyl arsine oxide hydroch oride with sodiumcarbonate. United States Patent No. 2-,222,384, issued November 19,1940, describes a mixture of 3'-'aminoi-hydroxy phenyl dichloro-arsinehydrochloride with sodium carbonate.

The principal object of the present invention is to provide a drymixture of solid arsenical with a buffering a ent thereby obtaining apreparation of improved stability and one which. when dissolved inwater. forms a therapeutically useful solution having improvedproperties;

We have discovered that improved "preparations result when the trivalentarsenical, such as' 3-amlno-4-hydroxy phenyl arsine oxide hydroof theadded substances.

The following examples further invention:

" Example 1 .040 gm. of dry-3-amino-4-hydroxy phenyl dichio'roarsinehydrochloride are mixed with .15 gm. of dry anhydroussodium s'uccinateor malonate and ampuled. or packaged in any othersuitable more or lessmoisture-proof container- On dissolving the mixture in10 cc. of

a water, the solution will be isotonic and have a chloride and"3-amino-4-hydroxv phenyl di- 1 chloroarsine hydrochloride, isassociated with a pH of 5.4. Y

' 1 Example 2 .045 gm. of dry 3-amino-4-hydroxy phenyl dichloroarsinehydrochloride are mixed with .150 gm. of dry, anhydrous sodium citrateand packaged. On solution in 10 cc. ofwater, the mixture will beisotonicand have a pH of 5.3.

Example 3 .045 gm. Of dry 3-amino-4-hydroxy .phenyl di- 'chloroarsincehydrochloride, .140 gm. of dry, an-

hydrous .disodium phosphate and .0244 gm. of

illustrate the citrate.

dry, anhydrous citric acid are mixed and packaged. On mixing with 10 cc.of water, the resuiting solution will have a pH of 8.4.

Example 4 .040 "gm. of dry 3-amino-4-hydroxy 'phenyl arsine oxidehydrochloride are mixed and packaged with 0.100 gm. of dry, anhydroussodium citrate. When the mixture is dissolved in .10 cc. of watentheresulting solution will have a pH of 5.6. The arsenical appears to bepresent in the solution almost completely in the undissociated citrate.p

The preferred preparation or our invention is that given in.Example 2above where the arsenical is 3-amino-4-hydroxy phenyl dichloroarsinehydrochloride .and the huflfer agent is sodium We claimi- I 1. Aspirocheticidal preparation comprising an arsenical oi the classconsisting of 3-amino-t- 2. A spirocheticidai preparation an arsenicalo! the class .or8-amino-ithe form of 'lmirow phenyi'arsine oxidehydrohalide and 3- amino-4-hydroxy phenyl dihalo arsine hydrohalideassociated with sodium citrate in. amount suflicient to maintain aninjectabie solution or a mixture or said substances at a pH value be--"tween 4.5 and 6.5. r

3. A spirocheticidai preparation comprising 3- 'amino-a hydroxy 'phenyldichloroarsine hydrochloride associated with sodium citrate in amountsufllcient to maintain an injectable solution of a mixture of saidsubstances at a pH value hetween 4.5 and 6.5.

hydroxy phenyi arsine oxide hydrohalide and 3- 4. A pharmaceuticalpreparation. comprising a dry mixture of 3-amino-4-hydroxy phenyidichloroarsine hydrochloride and a greater than equivalent proportion ofsodium citrate, said mixturewhen dissolved in water having a pH valuebetween 4.5 and 6.5v

6. A pharmaceutical preparation comprising a dry mixture 0!3-amino-4-hydroxy phenyl arsine oxide irvdrochloride and acreater thanequivalent proportion of sodium citrate, said mixture when dissolved inwater having a pH value hetween/1.5 and 6.5.

HOPHNSON.

- an v. 'rois'rooonov.

